Reversible pegylated drugs

a pegylated drug and reverse pegylation technology, applied in the field of reversible pegylation of drugs and to pegylated drugs, can solve the problems of major potential drawbacks, drastic loss or even abolishing of biological and pharmacological potencies of proteins, and the technology suffers from a principal drawback, and achieves the effect of prolonging the half-life of the circulating cycl

Active Publication Date: 2006-08-03
YEDA RES & DEV CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0013] It has been found, in accordance with the present invention, that drugs with a prolonged circulating half-life can be obtained by combining the technology of derivatization of the drug with Fmoc or FMS or similar moiet...

Problems solved by technology

In spite of the profound advantages often gained by pegylating therapeutic proteins, this technology suffers from a principal drawback.
On the other hand, the steric interference of the PEG chains often leads to a drastic loss or even abolish the biological and the pharmacological potencies of the proteins in the conjugates (Fuertges and Abuchowski, 1990; Katre, 1993; Bailon and Berthold, 1998; Nucci et al., 1991; Delgado et al., 1992; Fung et al., 1997; Reddy, 2000; Veronese, ...

Method used

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  • Reversible pegylated drugs
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Examples

Experimental program
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example 1

Synthesis of PEG5,000-Fmoc-OSu (Precursor 1)

[0216] Precursor 1 of the formula depicted in Scheme 1 was prepared starting from 2-aminofluorene and t-Boc-alanine (BocAla) by several steps, as depicted in Scheme 2.

1(a). Synthesis of 2-(t-BocAla-amino)fluorene (Intermediate a)

[0217] t-Boc-Ala (4.16 gr, 22 mmol) was dissolved in 11 ml dioxane. N,N′-Dicyclohexylcarbodiimide (DCC) (11 mmol in 11 ml 1 M DMF) was then added and the reaction was carried out for 3 hours at 25° C. under stirring. Dicyclohexylurea (DCU) formed was removed by centrifugation. The symmetrical anhydride product thus obtained (t-Boc-Ala-anhydride) was reacted overnight under stirring with 2-aminofluorene (0.925 g, 11 mmol) in 30 ml dioxane-water (1:1, v:v) containing 11 mmol of NaHCO3. The white solid formed was collected and dried under P2O5 in vacuum for 24 hours. Intermediate a was obtained in 60% yield (1.31 g, 3.34 mmol). It migrated on TLC (dichloromethane) with Rt=0.17. Mass-spectroscopy revealed a mass of ...

example 2

Synthesis of PEG5,000-FMS-OSu (Precursor 2)

[0224] Precursor 2, PEG5,000-FMS-OSu, depicted in Scheme 1, was prepared by sulfonation of Precursor 1, PEG5,000-Fmoc-OSu, with chlorosulfonic acid, as depicted in Scheme 2. Briefly, to a solution of Precursor 1 in 4.0 ml CH2Cl2, cooled to 0° C., a solution of ClSO3H in CH2Cl2 was added dropwise over a period of 15 min and the solution was stirred for 2 hours at 25° C. The product, PEG5,000-FMS-OSu, sulfonated at position 2 of the fluorene ring, was purified by preparative HPLC-procedure, and characterized by mass spectroscopy, elementary analysis (for sulfur), following extensive dialysis, and for its rate of hydrolysis (at pH 8.5, 37° C.) following conjugation to either gentamicin or insulin.

example 3

Synthesis of PEG40000-Fmoc-OSu (Precursor 3)—

[0225] Precursor 3, PEG40000-Fmoc-OSu, depicted in Scheme 1, was prepared as described in Example 1, steps 1(e) and 1(f), but replacing PEG5000-OSu with PEG40000-OSu under the same reaction conditions.

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Abstract

Reversible pegylated drugs are provided by derivatization of free functional groups of the drug selected from amino, hydroxyl, mercapto, phosphate and/or carboxyl with groups sensitive to mild basic conditions such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), to which group a PEG moiety is attached. In these pegylated drugs, the PEG moiety and the drug residue are not linked directly to each other, but rather both residues are linked to different positions of the scaffold Fmoc or FMS structure that is highly sensitive to bases and is removable under physiological conditions. The drugs are preferably drugs containing an amino group, most preferably peptides and proteins of low or medium molecular weight. Similar molecules are provided wherein a protein carrier or another polymer carrier replaces the PEG moiety.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation-in-part application of PCT application No. PCT / IL2004 / 000321, filed Apr. 8, 2004, in which in the US is designated, and claims the benefit of U.S. Provisional Patent Application No. 60 / 460,816, filed Apr. 08, 2003, the entire contents of each and both these applications being hereby incorporated by reference herein in their entirety as if fully disclosed herein.FIELD OF THE INVENTION [0002] The present invention relates to reversible pegylation of drugs and to pegylated drugs that are slowly converted to the drugs in physiological conditions. [0003] Abbreviations: ANP, atrial natriuretic peptide; t-Boc, tert-butyloxycarbonyl; BSA, bovine serum albumin; DCC, N,N′-dicyclohexylcarbodiimide; DCU, N,N′-dicyclohexylurea; DMF, N,N′-dimethylformamide; DTNB, 5,5-dithiobis(2-nitrobenzoic acid); ESMS, electrospray ionization mass spectra; Fmoc, 9-fluorenylmethoxycarbonyl; Fmoc-OSu, Fmoc-N-hydroxysuccinimid...

Claims

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Application Information

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IPC IPC(8): A61K38/28A61K38/22A61K38/21A61K38/19C07K14/575C07K14/535C07K14/56A61KA61K38/00A61K38/43
CPCA61K47/48215C07D207/404C07D207/416A61K38/22C07D403/12A61K38/26A61K38/28C07D207/452A61K31/7036A61K38/1709A61K38/212A61K38/2242A61K38/2278A61K38/27A61K47/60A61P3/04A61P3/06A61P3/08A61P3/10A61P5/02A61P9/04A61P9/12A61P11/16A61P13/12A61P31/12A61P35/00A61K47/54A61K47/545
Inventor SHECHTER, YORAMFRIDKIN, MATITYAHUTSUBERY, HAIM
Owner YEDA RES & DEV CO LTD
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